Viral Haemorrhagic Fevers

oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

Synonym: VHF

This disease is notifiable in the UK, see NOIDs article for more detail.

The viral haemorrhagic fevers (VHFs) are caused by four types of ribonucleic acid (RNA) virus:

  • Filoviruses cause Ebola and Marburg.
  • Arenaviruses cause Lassa fever, Argentine haemorrhagic fever (HF), Bolivian HF, Brazilian HF and Venezuelan HF.
  • Bunyaviruses cause Korean HF (Hantavirus), Rift Valley fever (RVF) and Crimean-Congo HF (CCHF).
  • Flaviviruses cause yellow fever and dengue fever.

Ebola virus, Marburg virus, Lassa fever, Hantavirus, yellow fever and dengue fever have their own articles in which they are covered in rather more detail. They are all highly infectious and lead to a potentially fatal disease with fever, malaise, vomiting, mucosal and gastrointestinal bleeding, oedema, and hypotension.

Filoviridae

This group includes the Marburg and Ebola viruses. Most outbreaks are in, or originate from, Africa. In the Congo and in Kenya, bats have been implicated as a possible source of an outbreak of Marburg infection.[1][2] The mortality is often around 80% and healthcare workers are often amongst the victims. Marburg and Ebola are covered in more detail in their respective articles.

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Arenaviridae

The most significant of these viruses is Lassa fever. Lassa fever is transmitted directly to humans by rodents, insect bites, especially mosquitoes, from primates and from patients. Incubation period is 5-16 days. Nosocomial infection is very common where precautions against cross-infection are minimal. Medical staff are also at risk of catching it from patients. Up to 300,000 infections and 5,000 deaths from Lassa fever are estimated to occur yearly, the highest incidence occurring in Sierra Leone, Liberia and Guinea.[3] Lassa fever has been imported into Germany, the Netherlands, the UK and the USA by travellers from Africa on commercial airlines.[4] Other Arenaviridae have incubation periods of 7-15 days.

Bunyaviridae

They include Rift Valley fever (RVF), Crimean-Congo haemorrhagic fever (CCHF), and a number of Hantaviruses. RVF and CCHF are both spread by arthropods. They have incubation periods of 2-5 days and 3-12 days respectively. RVF is an important African pathogen that is transmitted to humans and livestock by mosquitoes and by the slaughter of infected livestock.[5] CCHF virus is carried by ticks and causes a fulminant disease that can be transmitted by aerosol particles. Outbreaks of CCHF have occurred in Africa, Asia and Europe.

Hantaviruses exist throughout the world, causing two main syndromes. They are haemorrhagic fever with renal syndrome (HFRS) and Hantavirus pulmonary syndrome (HPS). They are divided into Old World Hantaviruses like the Korean virus, which usually cause HFR, and New World Hantaviruses that cause HPS. Both are transmitted by rodents. A new Hantavirus that was called Sin Nombre virus, caused an outbreak of highly lethal HPS in the southwestern USA in 1993. Sin nombre is Spanish for 'without name'. Incubation periods for Hantavirus infection are in the range of 9-35 days.

A recent steep increase in reported Hantavirus infections was noted in a known endemic area in southern Germany. This was thought to be due to an increase in the population of the natural animal reservoir - the bank vole.[6]

Flaviviridae

Yellow fever and dengue fever are the best known diseases caused by this group. Mosquitoes are the vectors for both. Yellow fever is found in tropical Africa and South America and dengue fever is found in Asia, Africa and the Americas. It has recently been shown that dengue virus targets mannose receptors on macrophages.[7]

Although these are many different viruses spread throughout many parts of the world, they have much in common in terms of pathology and clinical manifestations. The basic problem in patients with VHF is increased vascular permeability. They affect the vascular system, initially causing flushing, conjunctival injection and petechial haemorrhages, often with fever and myalgia. Later, obvious mucous membrane haemorrhage may occur, with hypotension, shock and circulatory collapse.

The severity of the disease may vary according to the virus, the viral load and the route of exposure. In acute infection, there is marked viraemia, and inadequate or delayed immune response may lead to rapid development of overwhelming viraemia. Infected organs may become necrotic. Haemorrhagic complications include hepatic damage (hence yellow fever), consumptive coagulopathy and primary marrow injury to megakaryocytes.

Multisystem organ failure can involve the haematopoietic system, the CNS and lungs and often accompanies vascular involvement. Hepatic involvement varies with the infecting organism and is at times seen with Ebola, Marburg, RVF, CCHF and yellow fever. Renal failure with oliguria is common in Hantavirus infection and may be seen in other VHFs as intravascular volume falls. Bleeding is marked with Ebola, Marburg, CCHF and the South American arenaviruses.

History

When seeing a patient with a strange and exotic disease, ask about foreign travel. Ask about exposure to rodents and insect bites, although these are not always remembered and aerosol transmission and other routes may be involved. For Ebola and Marburg virus the route of transmission is unknown. Family members and healthcare workers who have looked after the patient are at risk. If large numbers of people are suddenly affected, it must not be forgotten that these viruses have been developed in the past for biological warfare and a rogue state or terrorist organisation may be responsible.

Incubation period ranges from two days to three weeks. Complaints include:

  • High temperature, headache, myalgia and fatigue.
  • Abdominal pain and prostration.
  • In more advanced cases, haematemesis and bloody diarrhoea may occur.

Examination

Physical signs may vary from minimal to gross:

  • High temperature.
  • Pharyngitis, conjunctival injection.
  • Oedema, not dependent.
  • Rash may be petechial or ecchymoses.
  • Hypotension or shock.
  • Haemorrhage in mucous membranes.
  • In very advanced disease there may be altered mental state and circulatory collapse. This may be terminal.

There is much in common between the various haemorrhagic fevers but there are differences of emphasis between the typical symptoms and signs that may present.

Infected material is very dangerous and so investigations should be restricted to the necessary and specimens must carry warning labels, even if the diagnosis is only suspected and not yet confirmed. When the diagnosis has been made, it is a notifiable disease. Emerging and re-emerging diseases in Africa require good laboratory services that are often not available.[9]

  • FBC shows leukopenia and thrombocytopenia although this may not be so with Lassa fever.
  • LFTs show elevated transaminases and in Lassa fever this carries a high mortality.
  • Assessing bleeding tendency: partial thromboplastin time (PTT), INR and clotting times are all prolonged.
  • There may be evidence of disseminated intravascular coagulation. A recent study found that D-dimer levels were four times higher in patients who died from Ebola virus than in those who survived.[10]
  • With the exception of Hantavirus, most patients have viraemia at presentation and so it may be possible to use specific antibody tests to identify the virus.[11][12] Speed is often of the essence during outbreaks and high-throughput protocols for RNA extraction and quantitative reverse-transcription polymerase chain reaction (PCR) analysis have been developed to promote early recognition and surveillance during outbreaks.[13]
  • For Hantavirus, virus-specific IgM is usually assayed. Typing of a specific Hantavirus infection (necessary because of the difference in severity of symptoms of the various types) requires neutralisation antibody assays or reverse-transcription PCR and sequencing.[14]
  • A test assaying saliva IgM and IgG levels in dengue fever is being investigated.[15]
  • A concerted effort by all agencies involved in the management of an outbreak has a beneficial effect on clinical outcomes and on the containment of infection. For example, in 2005, the independent humanitarian medical aid agency Médecins Sans Frontières, together with the World Health Organization and the Angolan Ministry of Health, responded to the Marburg haemorrhagic fever (MHF) outbreak to contain the epidemic and care for those infected. This response included community epidemiological surveillance, clinical assessment and isolation of patients with MHF, safe burials and disinfection, home-based risk reduction, peripheral health facility support, psychosocial support, and informational and educational campaigns.[16]
  • Patients require barrier nursing and those in proximity should wear face masks and eye shields. Visitors should be restricted.
  • Intravenous fluids may be required and sometimes even blood or blood products. Oxygen may also be necessary.
  • Avoid intramuscular injections and aspirin because of bleeding.
  • Lassa fever and haemorrhagic fever with renal syndrome (HFRS) due to Hantavirus infection respond to the antiviral ribavirin. Ribavirin might be suitable for other arenaviruses and bunyaviruses but treatment must be started early. Ribavirin also is recommended for post-exposure prophylaxis. Antivirals are of no value for Ebola or Marburg fever.

These include retinitis, orchitis, hepatitis, transverse myelitis and uveitis. In those who recover from Lassa fever, deafness is the most common complication. Miscarriage is also common. Renal insufficiency occurs in HFRS infection.

Fatality rates vary from less than 10% in dengue fever to around 90% with Ebola-Zaire virus. An outbreak of Ebola virus occurred in 2001 in Uganda. The mortality rate was 36%; this lower rate was thought to be due to better infrastructure and more experienced care than that seen in previous outbreaks.[17]

Education and control programmes for rodents and mosquitoes are required in endemic areas.[18] There needs to be adequate training of healthcare workers regarding diagnostics, intensive care of patients under isolation, contact tracing, adequate precautionary measures in handling infectious laboratory specimens, control of the vector, and care and disposal of infectious waste.[19]

Yellow fever vaccine is extremely effective and a very safe vaccine but the only currently available vaccine for this group of diseases. It has been effectively incorporated into childhood vaccination programmes in Africa and endemic areas of South America but uptake is still patchy in non-endemic areas.[20] An effective vaccine for Lassa fever is a possibility.[4][21] Computer models using variables such as rainfall and temperature have been used to predict likely risk areas for Lassa fever in West Africa.[22]

Syndromic surveillance (the surveillance of a population using symptom groups) has been used by the military to detect possible biological warfare activity and was used to detect an early outbreak of dengue fever in French Guyana in 2006.[23]

Good progress is being made on a vaccine for Ebola virus; a recent study has demonstrated ability to cope with changes in Ebola glycoproteins.[24]

  • Lassa fever first appeared in Lassa in Nigeria in 1969.
  • Ebola virus first was described in 1976 after outbreaks of illness were reported along the Ebola River in Zaire (now the Democratic Republic of the Congo) and Sudan. Sporadic outbreaks continue, usually in isolated areas of central Africa. In 1995, an outbreak in Kikwit, Zaire led to 317 confirmed cases, with an 81% mortality rate. Two thirds of the cases were health workers caring for infected people. An outbreak in Uganda in late 2000 produced 425 cases and claimed 225 lives. Ebola virus has four subtypes: Ebola-Zaire, Ebola-Sudan, Ebola-Ivory Coast and Ebola-Reston. The last causes illness only in non-human primates.
  • Marburg virus was named after the German town where it first was reported in 1967 but it is traced to central Africa. As with Ebola, the natural host is unknown. Marburg virus was contracted by a traveller to central Africa in 1987 and has been endemic since 1998 in Durba, Democratic Republic of the Congo and in people working in goldmines.
  • Yellow fever and dengue fever have been known for rather longer and have had devastating effects on historical military campaigns. It is thought that yellow fever was brought to America by infected slaves from Africa. It is thought that the first reported epidemic was in 1648 in Mexico. An epidemic in Philadelphia in 1793 killed 10% of the city's 400,000 people. The control of mosquitoes to control yellow fever was an essential component of the project that made it possible to dig the Panama Canal.
  • Korean haemorrhagic fever was so named as it first came to prominence in the Korean War in 1951 when around 3,000 soldiers developed a disease characterised by fever and renal failure, with a fatality rate of 10%. It took until 1976 to identify the virus.[25] 

Further reading & references

  1. Swanepoel R, Smit SB, Rollin PE, et al; Studies of reservoir hosts for marburg virus. Emerg Infect Dis. 2007 Dec;13(12):1847-51.
  2. Kuzmin IV, Niezgoda M, Franka R, et al; Marburg virus in fruit bat, Kenya. Emerg Infect Dis. 2010 Feb;16(2):352-4.
  3. Khan SH, Goba A, Chu M, et al; New opportunities for field research on the pathogenesis and treatment of Lassa fever. Antiviral Res. 2007 Dec 17;.
  4. Geisbert TW, Jones S, Fritz EA, et al; Development of a new vaccine for the prevention of Lassa fever. PLoS Med. 2005 Jun;2(6):e183. Epub 2005 Jun 28.
  5. Rift Valley Fever; Weekly Epidemiological Record No. 2, 2008, 83, 17–24
  6. Faber M, Ulrich R, Frank C, et al; Steep rise in notified hantavirus infections in Germany, April 2010. Euro Surveill. 2010 May 20;15(20). pii: 19574.
  7. Miller JL, Dewet BJ, Martinez-Pomares L, et al; The Mannose Receptor Mediates Dengue Virus Infection of Macrophages. PLoS Pathog. 2008 Feb 8;4(2):e17.
  8. Mackow ER, Gavrilovskaya IN; Hantavirus regulation of endothelial cell functions. Thromb Haemost. 2009 Dec;102(6):1030-41.
  9. Shears P; Emerging and reemerging infections in africa: the need for improved laboratory services and disease surveillance. Microbes Infect. 2000 Apr;2(5):489-95.
  10. Rollin PE, Bausch DG, Sanchez A; Blood chemistry measurements and D-Dimer levels associated with fatal and nonfatal outcomes in humans infected with Sudan Ebola virus. J Infect Dis. 2007 Nov 15;196 Suppl 2:S364-71.
  11. Towner JS, Rollin PE, Bausch DG, et al; Rapid diagnosis of Ebola hemorrhagic fever by reverse transcription-PCR in an outbreak setting and assessment of patient viral load as a predictor of outcome. J Virol. 2004 Apr;78(8):4330-41.
  12. Emmerich P, Thome-Bolduan C, Drosten C, et al; Reverse ELISA for IgG and IgM antibodies to detect Lassa virus infections in Africa. J Clin Virol. 2006 Dec;37(4):277-81. Epub 2006 Sep 25.
  13. Towner JS, Sealy TK, Ksiazek TG, et al; High-throughput molecular detection of hemorrhagic fever virus threats with applications for outbreak settings. J Infect Dis. 2007 Nov 15;196 Suppl 2:S205-12.
  14. Vapalahti O, Mustonen J, Lundkvist A, et al; Hantavirus infections in Europe. Lancet Infect Dis. 2003 Oct;3(10):653-61.
  15. Chakravarti A, Matlani M, Jain M; Immunodiagnosis of dengue virus infection using saliva. Curr Microbiol. 2007 Dec;55(6):461-4. Epub 2007 Sep 27.
  16. Roddy P, Weatherill D, Jeffs B, et al; The Medecins Sans Frontieres intervention in the Marburg hemorrhagic fever epidemic, Uige, Angola, 2005. II. lessons learned in the community. J Infect Dis. 2007 Nov 15;196 Suppl 2:S162-7.
  17. Ebola outbreak in Uganda; Afrol News March 2001
  18. Bonner PC, Schmidt WP, Belmain SR, et al; Poor housing quality increases risk of rodent infestation and Lassa fever in refugee camps of Sierra Leone. Am J Trop Med Hyg. 2007 Jul;77(1):169-75.
  19. Ogbu O, Ajuluchukwu E, Uneke CJ; Lassa fever in West African sub-region: an overview. J Vector Borne Dis. 2007 Mar;44(1):1-11.
  20. Monath TP; Yellow fever as an endemic/epidemic disease and priorities for vaccination. Bull Soc Pathol Exot. 2006 Dec;99(5):341-7.
  21. Fisher-Hoch SP, Hutwagner L, Brown B, et al; Effective vaccine for lassa fever. J Virol. 2000 Aug;74(15):6777-83.
  22. Fichet-Calvet E, Rogers DJ; Risk maps of Lassa fever in West Africa. PLoS Negl Trop Dis. 2009;3(3):e388. Epub 2009 Mar 3.
  23. Meynard JB, Chaudet H, Texier G, et al; Value of syndromic surveillance within the Armed Forces for early warning during BMC Med Inform Decis Mak. 2008 Jul 2;8:29.
  24. Hensley LE, Mulangu S, Asiedu C, et al; Demonstration of cross-protective vaccine immunity against an emerging pathogenic PLoS Pathog. 2010 May 20;6(5):e1000904.
  25. Klein SL, Calisher CH; Emergence and persistence of hantaviruses. Curr Top Microbiol Immunol. 2007;315:217-52.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Laurence Knott
Current Version:
Peer Reviewer:
Dr Helen Huins
Last Checked:
28/06/2013
Document ID:
2921 (v25)
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